Process of preparing substituted propionic acids



Patented June 1949 PROCESS OF PREPARING SUBSTITUTED PROPIONIC ACIDS 1 Robert D. Babson, Railway, N. J., assignor to Merck & (20., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Original application July 12, 1946,

Serial No. 683,143. Divided and this application February 28, 1947, Serial No. 731,719

1 Claim. 1

This invention is concerned generally with novel chemical processes: more particularly it relates to an improved method for the manuiacture of alkyl esters of a-halo-pfl-dialkoxyproplonic acid, useful in the preparation of ai'ormyl-phenaceturamide, a primary intermediate in the synthesis of pencillin.

This application is a division of my co-pending application Serial No. 683,143, filed July 12, 1946, now U. S. Patent 2,459,059.

It is now discovered, in accordance with the present invention, that alkyl esters of a-halofl,fl -dialkoxy-propionic acid (2) can be synthesized by reacting an alkyl fl-acyloxy-acrylate (1') with a halogen and an aliphatic alcohol. This reaction may be chemically represented as follows: i

a-o XI a-o O-OCH=CH-CO on CH-OHC on ROH plications, Serial No. 728,724, filed February 14,.

1947, and Serial No. 710,945, filed November 19, 1946. For example methyl acetate can be condensed with methyl formate and sodium to form methyl a-(sodio-formyl)-acetate; this can then be treated with acetyl chloride to produce methyl fi-acetoxy-acrylate. When this compound is reacted with chlorine and methyl alcohol, and the product obtained treated as described in the above co-pendina applications, the product is methyl a-phenacetamido-fi,fi-dimethoxy propionate. It is converted to a-formyl-phenaceturamide according to processes described in detail in copending application, Serial No, 636,516, filed December 21, 1945.

It is known that ethyl a-bromo-fl,fl-diethoxypropionate can be prepared by reacting ethyl asodio tormyl acetate with bromine and ethanol, but the yields obtainable according to this process 'propionate in yields of over 80% I 2 have been limited to about 20% of theory. There is no indication in the prior art that an alkyl ahalo-flfl-dialkoxy-propionate could be prepared by treatment of an alkyl fi-acyloxy-acrylate.

- It is now discovered, according to, the present invention, that alkyl p-acyloxy-acrylates can be reacted with a halogen and an aliphatic alcohol to produce the desired alkyl d-halo-pfi-dialkoxy of theory. Moreover alkyl fi-acyloxy-acrylates can be prepared in yields of approximately 60% of theory by reacting alkyl a-(metallo-formyl) -acetates with aliphatic acyl halides. It is thus possible according to my novel improved process to convert alkyl (a-metallo-formyl)-acetates to the corresponding alkyl a-haIO-fifi-dMIROXy propionates in yields of approximately 50% of theory.

In carrying out the reaction, the alkyl fl-acyloxy acrylate is dissolved in an aliphatic alcohol such as ethyl alcohol, methyl alcohol, butyl alcohol and the like; and a quantity of halogen such as chlorine, bromine and the like; substantially equimolecular to the acrylic acid derivative is plonate, in substantially pure form.

The following example illustrates a method 01' carrying out the present invention, but it is to be understood that this example is given by way of illustration and not of limitation.

Example A solution of about 100 g. of ethyl fl-acetoxyacrylate in about 190 g. of absolute ethanol is cooled to approximately -5 0.; about 45.2 g. of chlorine is added over approximately a 1 hour period and the resulting mixture is allowed to stand for approximately 15 hours at room temperature. The reaction product is poured into an equal volume of ice water mixed with about 200 cc. of ether, the layers are separated and the water is extracted once with ether. The combined ether extracts are washed free of water soluble acidic materials with ice water, dried over sodium sulfate and the ether evaporated under reduced pressure. The residual oil is vacuum distilled to produce approximately 117 g. of ethyl oz-ChlOIO- p,fi-diethoxy-propionate; B. P. 87-91 C. at 3 8 mm. n"=1.4252; yield approximately 83% of theory based on ethyl p-acetoxy-acrylate.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and it is to be understood that the invention is to be limited only by the appended claim.

I claim:

The process which comprises reacting altogether ethyl p-acetoaqr acrylate, chlorine and ethyl alcohol to produce ethyl a-chloro-mp-diethoxy propionate.

ROBERT D. BABSON.

REFERENCES CITED Pechmann, Ber. deut. chem, vol. 25 (1892), pa es 1048-1050.

Sugasawa, Chem. Zemt, 1927, vol. II, page 1814.

Croshnik et aL, J. Am. Chem. 800., vol. 07

(May 1945). pages 722-723.

' Merck Report 12d, February 18, 1944 (September 27, 1945) P ge 5. 

